Cryptococcus neoformans is an opportunistic fungal pathogen of man. In preliminary studies designed to explore the hypothesis that resistance to oxidative killing may contribute to the virulence of this organism, we have isolated a novel class of mutants of Cryptococcus sensitive to hyperbaric oxygen. Genetic characterization of these mutants has thus far defined at least three loci involved in this phenotype. Interestingly, one locus was found to be required for production in melanin, a known virulence factor, but one whose role in pathogenesis is not understood. We propose physiological, genetic and biochemical experiments to elucidate the relationship between melanin and resistance to oxidative stress. In addition, we will pursue molecular biological studies to define the regulation of production of phenoloxidase, the enzyme involved in formation of cryptococcal melanin.